Systemic lupus erythematosus associated with multiple myeloma: Two case reports and a literature review

Abstract Introduction Systemic lupus erythematosus (SLE) complicated by multiple myeloma (MM) is a relatively rare clinical presentation, and is easily ignored due to their similar or even identical manifestation, which may lead to misdiagnosis and mistreatment. Case report We report two cases of SLE with MM. Case 1 was a 59‐year‐old male who was diagnosed with SLE 11 years ago. Abnormal kidney function was detected 4 months ago and a bone marrow aspirate revealed MM. He then received three cycles of bortezomib, dexamethasone, and chemotherapy with liposomal doxorubicin, and one cycle of lenalidomide plus dexamethasone. He died of infectious shock. Case 2 was a 58‐year‐old female who was diagnosed with SLE 27 years ago. After the onset of abnormal renal function 4 years ago, the patient was still treated according to SLE disease activity. When renal function rapidly deteriorated, serum and urine immunofixation electrophoresis was positive for IgG γ with free light chains and she was diagnosed with SLE complicated by MM. She did not agree to the treatment for MM as advised and was discharged from the hospital against medical advice. Case 2 died of cardiac failure. Thirteen cases of SLE with MM reported from 2000 to 2022 in PUBMED and Mendeley and our above two cases were reviewed. Among the 15 patients, 13 were females and 2 were males. The median age at the time of SLE with MM diagnosis was 50 years, and the median time to a delayed diagnosis was 7 years. The serum monoclonal immunoglobulin level was elevated and extramedullary manifestations of renal dysfunction were common. Conclusions An elevated monoclonal immunoglobulin level or newly unexplained renal dysfunction occurring in a patient with SLE should prompt monitoring and further screening of MM, rather than treatment as a secondary manifestation of SLE.


| INTRODUCTION
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory connective tissue disease that affects multiple organs and occurs mostly in young women. Quantitative studies have shown that genetic, endocrine, infectious, immune dysfunction, and environmental factors are related to the pathogenesis of SLE. 1 The association between SLE and lymphoproliferative syndromes is frequently reported in the literature. 2 Multiple myeloma (MM) is a malignant plasma cell disorder in which tumor cells originate from plasma cells in the bone marrow. 3 B lymphocytes develop to their final functional stage as plasma cells, thus MM is designated as a plasmacytoma (i.e., a single B cell lymphoma). 3 SLE is usually reported to be associated with different types of plasma cell disorders, such as monoclonal gammopathy of undetermined significance (MGUS) and amyloid degeneration. Some patients with MGUS progress to MM. Among SLE patients, the incidence of MGUS ranges between 2.2% and 3.3%. 4,5 Ali et al. 6 reported that the incidence of MGUS in SLE patients is up to 5.4%, which is higher than the general population. Moreover, monoclonal IgG is the most common type. 5 Although the incidence of MGUS is higher in SLE patients than general population, the coexistence of SLE and MM is rarely reported, and large population-based studies are lacking. We report two cases in which MM occurred 11 and 27 years after the onset of SLE in our hospital, a large comprehensive public hospital with 4990 open beds and 5.85 million outpatient visits annually. Delayed diagnosis of co-existing of SLE and MM need more concerns on this disease. We also analyzed the clinical data of previously published related cases to describe the clinical features of MM in SLE patients. A 59-year-old male was admitted to our hospital in May 2021 due to "joint swelling and pain with fever for 11 years, and abnormal kidney function diagnosed 4 months ago." This patient was diagnosed with SLE in 2011 (11 years ago) with joint swelling and pain as presenting symptoms, decreased white blood cell and platelet counts, and positivity for several autoantibodies (ANA: positive; Resistance to DS-DNA: positive). No family history of SLE, no history of serious illness and mental illness was reported by the patient. The physical examination on admission was unremarkable. The patient was given prednisone acetate (60 mg/day), which was then tapered to 5 mg/day. Hydroxychloroquine (200 mg/day) and cyclosporine (150 mg/day) were given. The health status of the patient remained stable between 2016 and 2020. He discontinued the use of cyclosporin for 4 years; however, abnormal kidney function was detected during an outpatient follow-up visit in March 2021 with the following laboratory findings: monoclonal immunoglobulin, increased; serum creatinine (SCr), 101.0 ummol/l; blood urea nitrogen (BUN), 5.33 mmol/L; uric acid, 333 mmol/L; immunoglobulin G (IgG), 23.84 g/L; immunoglobulin A (IgA), 0.86 g/L; immunoglobulin M (IgM), 0.67 g/L; C3, 0.50 g/L; urine protein, negative; erythrocyte sedimentation rate (ESR), 70; Creactive protein (CRP), 80.20; white blood cell (WBC) count, 5.37 × 10 9 /L; red blood cell (RBC) count, 3.77 × 10 12 /L; hemoglobin (Hb),116 g/L; and platelet (PLT) count,165 × 10 9 /L. In consideration of SLE activity, prednisone was increased to 20 mg daily. Cyclophosphamide (CTX), 0.4 g every 2 weeks, was administered 4 times. The patient's fatigue did not improve and he was admitted to our hospital on 29 May 2021. The admission examination revealed the following: negative for urine protein; ESR, 59 mm/h; creatinine, 230 μmol/L; BUN, 15.07 mmol/L; uric acid, 677 μmol/L; IgG, 24.55 g/L (normal range, 7.60-16.60 g/L); IgA, 0.9 g/L (normal range, 0.71-3.35 g/L); IgM: 0.79 g/L (normal range, 0.48-2.12 g/L); C3, 0.5 g/L; 24-h urine total protein, 0.27 g/d; and calcium, 1.89 mmol/L. Serum and urine immunofixation electrophoresis was positive for IgG λ with free light chains. A bone marrow aspirate revealed MM. He was transferred to the Department of Hematology and received three cycles of bortezomib, dexamethasone, and chemotherapy with liposomal doxorubicin. No bone marrow improvement was achieved after three cycles with double-checks and review. He later received one cycle of lenalidomide plus dexamethasone but died of infectious shock on December 1, 2021. The timeline of Case 1 is shown in Table 1.

| Case 2
A 58-year-old female was admitted to our hospital in January 2022 due to a "diagnosis of SLE for 27 years and abnormal kidney function for 4 years, with exacerbation of symptoms for 1 week." No family history of SLE, no history of serious illness and mental illness was reported by the patient. The physical examination on admission showed the patient to be overweight with a blood pressure of 200/100 mmHg, an anemic appearance, and mild edema of the lower limbs. She was diagnosed with SLE in 1994 (27 years ago) at another hospital, with facial erythema, proteinuria, positivity for antinuclear antibody (ANA), and thrombocytopenia as presenting symptoms. She was prescribed 60 mg-10 mg/day of CTX, mycophenolate mofetil (0.75 g bid), and hydroxychloroquine (300 mg/d) for long-term use. After the patient was stabilized, the immunosuppressive drugs were discontinued for nearly 10 years, except for prednisone acetate (10 mg/day) plus hydroxychloroquine (300 mg/d). The patient presented with abnormal kidney function in April 2018 at another hospital, with 2-3 + urine protein.
The 24-h urine total protein was 1.06-1.43 g. No treatment was offered. The following clinical data were available in July 2019: creatinine, 175 μmol/L; BUN, 16.18 mmol/L; uric acid, 580 μmol/L; calcium and phosphorus, normal range; urine protein, 2+; and cylindruria, negative. The following clinical data were available in September 2019: creatinine, 150 μmol/L; BUN, 13.8 mmol/L; uric acid, 568 μmol/L; C3, 0.74 g/l; IgG, 22.13 g/L (normal range, 7.60-16.60 g/L); IgA, 1.51 g/L (normal range, 0.71-3.35 g/L); and IgM, 0.37 g/L (normal range, 0.48-2.12 g/L). Active SLE was considered and the patient was given mycophenolate mofetil (MMF) (1.5 g/day for 8 months). The patient had a follow-up examination in March 2020 and the following clinical data were available: creatinine, 208 μmol/L; BUN, 17.2 mmol/L; uric acid, 557 μmol/L; and IgG, 21.09 g/L. The proteinuria did not improve on re-testing. Active SLE was considered, thus MMF was discontinued and the treatment was changed to CTX (0.4 g every 2 weeks for 6 months) however, the urine protein still fluctuated between 2+ and 3+. The following clinical data were available in August 2020: creatinine, 287 μmol/L; BUN, 19.6 mmol/L; uric acid, 452 μmol/L; and IgG, 20.93 g/L. CTX was continued (0.4 g every 2 weeks for 6 months). The following clinical data were available in May 2021: creatinine, 388 μmol/L; BUN, 29 mmol/L; uric acid, 630 μmol/L; serum calcium, 3.33 mmol/L (elevated); and IgG, 19.87 g/L. CTX was administered for 14 months and renal function did not improve. Due to a concern of chronic renal insufficiency, the immunosuppressant was discontinued and treatment was initiated to reduce kidney damage and control blood pressure (antihypertensive drugs: calcium antagonist + vasodilator). The following clinical data were available in  re-examined upon admission to our hospital in December 2021, with the following laboratory findings: ANA, 1:320; and extractable nuclear antigen (ENA), negative. The previous treatment was continued.
The patient was re-examined upon admission to our hospital in January 2022 with the following laboratory findings: creatinine, 776 μmol/L; BUN, 34.13 mmol/L; uric acid, 514 μmol/L; serum calcium, 3.5 mmol/L; IgG, 22.63 g/L; IgA 1.10 g/L; IgM, 0.25 g/L (below normal); and C3, 0.73 g/L. A diagnosis of MM was considered, and serum and urine immunofixation electrophoresis revealed positivity for IgG γ with free light chains. The diagnosis of MM was confirmed. The patient was advised to have MM treated in the Department of Hematology. She had a myocardial infarction and received treatment for myocardial infarction with aspirin and atorvastatin. The patient was very old with many underlying diseases, and her family members were concerned that the treatment was too difficult and costly with a low success rate. Therefore, the patient did not receive treatment for MM as advised. She was later discharged against medical advice. During a telephone follow-up on 7 February, a family member reported that the patient had died on February 3, 2022 due to cardiac failure. The timeline and examination results of Case 2 are shown in Table 2.

| LITERATURE REVIEW
Considering that the previous literature review before 2000 was outdated, the Pubmed and Mendeley databases were searched from January 2000 to January 2022 using the following search terms: "systemic lupus erythematosus"; and "multiple myeloma." The inclusion criteria for the selected articles were as follows: (i) definite diagnosis of SLE and MM; (ii) human studies; and (iii) articles published in English. Articles were excluded for the following reasons: (i) duplicate data were published from the same center; and (ii) reviews or meta-analyses. Based on the search results, one researcher reviewed the title and the abstract, then two authors confirmed the selected articles and read the full text. The authors analyzed and extracted the data independently and merged the two sets of data into one database. A discussion was arranged to resolve disputed data. The following information and outcome measures were obtained using a predesigned   5 1 was combined with myasthenia gravis and keratosis, 11 and 1 was combined with cutis laxa. 14 Except for 1 patient in whom SLE and MM were diagnosed simultaneously, 10 the other 14 patients with SLE were stable. SLE was generally treated by hormones plus hydroxychloroquine, although some patients were also treated with immunosuppressants, including tacrolimus, azathioprine, and CTX. 5,7,11 One case reported in the present study had discontinued the use of cyclosporin for 4 years and another case was treated with CTX and MMF. In the latter case, proteinuria recurred after discontinuation of immunosuppressants for 10 years. This patient was diagnosed with lupus nephritis, but unresponsive to the treatment with CTX and mycophenolate mofetil. MM primarily presents with microscopic hematuria, proteinuria, ostealgia, bone fractures, lymph node enlargement, an elevated serum calcium level, elevated monoclonal IgG, and abnormal kidney function.

| DISCUSSION
As reported, the incidence of MM in SLE patients is higher than the general population. 5 The meta-analysis by Song 15 showed that SLE increased the risk of MM (SIR = 1.48, 95% CI = 1.02-2.14); however, the literature search most often revealed sporadic case reports. Based on the literature review, with the exception of one patient in whom SLE and MM were diagnosed simultaneously, MM occurred several years after the diagnosis of SLE in all other patients. We reported herein two patients with SLE complicated by MM (one male and one female) occurring 11 and 27 years after the onset of SLE at 59 and 58 years of age, respectively. These results demonstrated that SLE may increase the risk of MM, and the diagnosis of MM can be missed or MM is easy to misdiagnosis.
The mean median time from the diagnosis of SLE to the diagnosis of MM was 7 years. The median age at the time of diagnosis of MM was 50 years in the present study. Okoli 8 reported that the median age of SLE with MM was 45 years. In another study, the median age at the time of diagnosis of MM was <64 years of age, which was the median age at the time of diagnosis of MM in the general population. 16 Our reported cases of SLE were diagnosed with MM at 59 and 58 years of age, respectively. The above facts imply that the genetic or immune factors related to SLE may influence the molecular transformation of MM. 9 The clinical features of SLE with MM differed from the clinical features of MM alone. Despite the higher incidence of MM in males than females, 17 87% (13/15) of the patients with SLE and MM were females, probably due to the fact that SLE predominantly affects females. SLE alone and MM alone are more common in the black population based on previous reports 18,19 ; however, only two patients with SLE and MM were black based on our literature review, while all other cases were Caucasians and Asians. SLE with MM does not predominantly affect blacks.
Extramedullary manifestations were more common. The growth and survival of myeloma cells depend on the bone marrow microenvironment. Extramedullary involvement observed in patients with MM alone usually indicates that the patients have progressed to the late stage or patients who have relapsed. Based on our literature review, the incidence of extramedullary involvement was higher in patients with SLE and MM. Among the 15 cases, 8 had extramedullary involvement, accounting for 53.3% (8/15). One study suggested that the high incidence of extramedullary involvement in SLE patients with MM might be related to the early onset of MM. 20 Extramedullary involvement was observed in 40% of the MM patients <55 years of age at the time of diagnosis. 20 According to another study, extramedullary involvement is related to activation of the B lymphocyte stimulator (BlyS), which further affects the growth and survival of MM cells. 21 High BlyS expression in SLE patients has an important impact on the growth and survival of MM cells. 21 The two patients reported in our study had long-term stable SLE, and immunosuppressants had been discontinued for many years. The two patients had no obvious bone lytic manifestations, such as bone pain, and both exhibited extramedullary manifestations of abnormal renal function, with decreased complement activity, accompanied by increased monoclonal globulin. Therefore, abnormal renal function was more likely to be misdiagnosed as the disease activity of SLE itself. Moreover, the abnormal renal function in Case 2 lasted 4 years from detection until the diagnosis of MM.
Therefore, when a patient with stable SLE exhibit abnormal renal function that cannot be explained by the primary disease, an elevated monoclonal immunoglobulin level, progressive elevation of one monoclonal globulin and/or associated decline of another clonal globulin, and a decreased ANA titer or even a change from positive to negative, the patient should not be simply treated for an active or secondary manifestation of SLE. Such patients must be examined and screened with immunostationary electrophoresis and bone marrow cells or biopsy to further confirm the diagnosis or diagnose suspected MM as early as possible. In addition, for patients who have already been diagnosed with MM, the presence of other autoimmune diseases, such as SLE, must also be considered due to the underlying correlations.
The potential pathogenesis of lymphoproliferative diseases associated with SLE has not been established; however, the following pathogenic mechanisms have been proposed 22 : B-cell hyperactivity and defective immune surveillance may help B-cell clones escape the immune system; increased resistance to cell apoptosis may further promote the malignant transformation of tumors; and mutations in the phosphatase and tensin homolog (PTEN) gene and Bcl-2 overexpression may be the basis for resistance to cell apoptosis. Among SLE patients, immunosuppressive therapy, continuous Epstein-Barr virus (EBV) infection, or other concurrent autoimmune diseases may increase the risk of malignancies. 22,23 Only 3 of 13 cases in the literature review were prescribed immunosuppressants. Both cases reported in the present study received one-time treatment with CTX/MMF; however, whether the use of cytotoxic drugs in patients with SLE can induce tumors is still unknown. The immune dysfunction associated with SLE has attracted much attention. Studies have shown that suppressor T-cell dysfunction and functional defects in NK cells may lead to an abnormal proliferative response of B cells to various autoantigens. In patients with SLE, T-and B-cell hyperactivity and continuous activation of B cells may be conducive to the appearance of abnormal or malignant plasma cell clones. The incidence of rheumatoid arthritis and SLE is higher in first-degree relatives of MM patients, thus indicating the effects of genetic factors. Landgren et al. 24 also reported an increased risk of MM in those with a family history of SLE (OR, 2.66; 95% CI, 1.12-6.32). The aunt of case number 11 died of MM at 50 years of age but had no history of SLE. None of the other patients had a family history of SLE or MM. The two cases reported in the present study had no genetic background or family history of SLE and MM. The heredity of SLE with MM is still waiting for further elucidation.
Currently, there are no specific guidelines for the treatment of SLE with MM. Because the conditions of cases in the previous reports and Case 1 in our report were stable with respect to SLE, the patients primarily received treatment for MM using the VAD regimen. Case 2 reported herein was once misdiagnosed with abnormal kidney function and proteinuria related to SLE. Therefore, the treatment targeting SLE was strengthened in this case; however, CTX was no longer used after the diagnosis of MM was made.

| SUMMARY
The diagnosis of MM is easily delayed or misdiagnosed in patients diagnosed with SLE. In stable SLE patients with extramedullary involvement, abnormal kidney function or an elevation of a monoclonal immunoglobulin level, SLE complicated with MM may be suspected. These patients must be examined and screened with immunostationary electrophoresis and bone marrow cells or biopsy to further confirm the diagnosis or diagnose suspected MM as early as possible.